KR101709608B1 - Preparation Method of Hyaluronate Fiber by Melt-Spinning and Hyaluronate Fiber Prepared Thereof - Google Patents

Preparation Method of Hyaluronate Fiber by Melt-Spinning and Hyaluronate Fiber Prepared Thereof Download PDF

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KR101709608B1
KR101709608B1 KR1020150125088A KR20150125088A KR101709608B1 KR 101709608 B1 KR101709608 B1 KR 101709608B1 KR 1020150125088 A KR1020150125088 A KR 1020150125088A KR 20150125088 A KR20150125088 A KR 20150125088A KR 101709608 B1 KR101709608 B1 KR 101709608B1
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hyaluronate
fiber
spinning
hyaluronate fiber
present
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KR1020150125088A
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Korean (ko)
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권동건
박승현
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(주)진우바이오
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Priority to KR1020150125088A priority Critical patent/KR101709608B1/en
Priority to PCT/KR2016/009748 priority patent/WO2017039335A1/en
Priority to US15/757,605 priority patent/US10994048B2/en
Priority to JP2018531277A priority patent/JP6563141B2/en
Priority to EP16842301.0A priority patent/EP3346032B1/en
Priority to CN201680051412.5A priority patent/CN108350610B/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/04—Surgical instruments, devices or methods, e.g. tourniquets for suturing wounds; Holders or packages for needles or suture materials
    • A61B17/06—Needles ; Sutures; Needle-suture combinations; Holders or packages for needles or suture materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/04—Surgical instruments, devices or methods, e.g. tourniquets for suturing wounds; Holders or packages for needles or suture materials
    • A61B17/06—Needles ; Sutures; Needle-suture combinations; Holders or packages for needles or suture materials
    • A61B17/06166—Sutures
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/06—At least partially resorbable materials
    • A61L17/10—At least partially resorbable materials containing macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/042—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/08—Melt spinning methods
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
    • D01F11/00—Chemical after-treatment of artificial filaments or the like during manufacture
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
    • D01F9/00—Artificial filaments or the like of other substances; Manufacture thereof; Apparatus specially adapted for the manufacture of carbon filaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
    • C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
    • D—TEXTILES; PAPER
    • D10—INDEXING SCHEME ASSOCIATED WITH SUBLASSES OF SECTION D, RELATING TO TEXTILES
    • D10B—INDEXING SCHEME ASSOCIATED WITH SUBLASSES OF SECTION D, RELATING TO TEXTILES
    • D10B2509/00—Medical; Hygiene
    • D10B2509/04—Sutures

Abstract

The present invention relates hyaluronate fiber, and more specifically, to hyaluronate fiber capable of being used in surgical suture, cosmetic filler, lifting thread, scaffold for tissue engineering, etc. According to the present invention, a method of manufacturing hyaluronate fiber by melt-spinning comprises the following steps: (a) adjusting the moisture content of hyaluronate with a molecular weight of 500 to 3,000 kDa within a range of 5 to 20%; (b) inserting the hyaluronate of which the moisture content is adjusted into a melt-spinning apparatus, heating the hyaluronate at 150 to 200C, and then performing spinning at high pressure to manufacture hyaluronate fiber; and (c) soaking the hyaluronate fiber in an aqueous ethanol solution to harden the surface thereof. According to the present invention, since the hyaluronate fiber is made of the hyaluronate as a main component, safety and biocompatibility are excellent. Moreover, the hyaluronate fiber is free from microorganism contamination when compared to general liquid hydrogel product, and is easy to be managed and used, and can thus be used as a material for tissue repair. Also, since the hyaluronate fiber is a solid type product, the volume is quite less with respect to the concentration of the hyaluronate, and thus can minimize pain and inconvenience of a patient when the hyaluronate fiber is injected inside the body, thereby maximizing curing effect.

Description

용융 방사에 의한 히알루론산염 파이버의 제조방법 및 이로부터 제조된 히알루론산염 파이버 {Preparation Method of Hyaluronate Fiber by Melt-Spinning and Hyaluronate Fiber Prepared Thereof}The present invention relates to a method for producing a hyaluronate fiber by melt spinning and a method for preparing a hyaluronate fiber by a melt spinning method,

본 발명은 히알루론산염 파이버에 관한 것으로, 더욱 상세하게는 수술용 봉합사, 성형 필러, 리프팅용 실, 조직 공학용 세포지지체(Scaffold) 등으로 활용 가능한 히알루론산염 파이버 및 이의 제조방법에 관한 것이다.
The present invention relates to a hyaluronate fiber, and more particularly, to a hyaluronic acid fiber capable of being used as a surgical suture, a molding pillar, a lifting thread, a cell scaffold for tissue engineering, and the like.

히알루론산(hyaluronic acid, HA)은 분자량이 500,000 내지 13,000,000Da에 이르는 무색의 고점도 다당류로서, 반복단위인 D-글루쿠론산과 N-아세틸 글루코즈아민이 (1-3)과 (1-4)로 번갈아 결합되어 있다. Hyaluronic acid (HA) is a colorless, highly viscous polysaccharide having a molecular weight of 500,000 to 13,000,000 Da. D-glucuronic acid and N-acetylglucosamine, which are repeating units, Respectively.

HA은 여러 가지 인체 생리 활성에 관여하며, 분자량에 따라 다양한 생리활성을 가지는 것으로 알려져 있다. 특히 고분자의 히알루론산은 인체 충진제 (space-filler)로 사용되고, 혈관생성 억제(anti-angiogenic), 면역 억제 (Immunosuppressive) 등의 기능을 가지는 것으로 알려져 있다.HA is involved in various physiological activities and has been known to have various physiological activities depending on the molecular weight. Particularly, hyaluronic acid of a polymer is used as a space-filler and is known to have functions such as anti-angiogenic and immunosuppressive functions.

따라서 현재 2.0MDa 이상의 HA을 사용하여 고점성의 하이드로겔 형태로 하여 관절 주사제와 성형 필러 및 내, 외과 수술용 유착 방지제로 많이 활용되고 있다. 그러나 대부분의 제품은 고점성 수용액 또는 하이드로겔의 액상 형태이어서 활용성, 보관성 및 가공성 측면에서 제한이 있다. 특히, 액상 형태로 활용 시 HA 자체의 안정성(Stability)이 떨어져 제품의 보관과 유통에 주의가 요구되며, 실제 제품 내의 HA 함유량은 1~5% 정도의 낮은 농도로, 환자 인체 내 투입 시 고농도 고용량 투입이 불가 할뿐만 아니라, 높은 체적 볼륨으로 인한 투입 압력으로 인해 환자에게 큰 고통이 수반되게 된다. Therefore, it is currently used as a high-viscosity hydrogel form using HA of 2.0 MDa or more and is widely used as an injecting agent for joints, a molding filler, and an anti-adhesion agent for internal or surgical operation. However, most of the products are in the form of liquid form of high viscosity aqueous solution or hydrogel, which limits the usability, storage and processability. In particular, when used as a liquid form, the stability of the HA itself deteriorates, and attention is paid to the storage and distribution of the product. The HA content in the product is as low as 1 to 5% In addition to the impossibility of input, the input pressure due to the high volume volume causes a great pain to the patient.

또한, HA를 액상 형태로 체내 투입 시, 체내에 존재하는 여러 분해 효소 등에 의하여 급속히 분해되어 분자량이 낮아짐으로써 체내 지속성 또한 낮아져 치료 부위에 대한 효과가 떨어지는 단점이 있다. In addition, when HA is injected into the body in the form of a liquid, it is rapidly degraded by various degrading enzymes present in the body to lower the molecular weight, thereby decreasing the persistence of the body, and the effect on the treatment site is deteriorated.

따라서, HA의 안정성, 활용성 등을 향상시키기 위하여, 한국공개특허 제2014-0100469호 및 일본 공개특허 제2011-31034호에서는 안전성이 입증된 분해성 고분자를 주원료로 하여 HA를 일부 소량, 10% 이내로 블렌딩 (Blending) 또는 코팅시킨 봉합사를 개시하였으나, HA의 함량이 낮은 문제점이 있었다.Therefore, in order to improve the stability and utility of HA, Korean Laid-Open Patent Application No. 2014-0100469 and Japanese Patent Laid-Open No. 2011-31034 disclose that a small amount of HA and less than 10% of HA are used as main raw materials, Blended or coated sutures were disclosed, but HA content was low.

HA 단독으로 파이버(fiber)를 제조하면 HA 함량을 늘릴 수 있겠지만, 일반적으로 HA 고분자 다당체 내의 강한 수소 결합에 기인한 용융 불가로 인하여 HA 자체만으로 파이버를 제조하는 방법은 아직까지 알려지지 않았다.
HA alone can increase the HA content, but generally it is not yet known how to manufacture the HA alone by virtue of the inability to melt due to the strong hydrogen bonding in the HA polymer polysaccharide.

이에, 본 발명자들은 상기 문제점을 해결하기 위하여 노력한 결과, 비 용융성의 히알루론산염을 전 처리로 수분 함량을 조절한 후, 용융 방사시킬 경우 수술용 봉합사, 성형 필러, 조직 공학용 세포지지체 (Scaffold) 등으로 활용 가능한 히알루론산나트륨 파이버(fiber)를 제조할 수 있다는 것을 확인하고, 본 발명을 완성하게 되었다.
Accordingly, the present inventors have made efforts to solve the above problems. As a result, the present inventors have found that when a non-melting hyaluronate is subjected to a pretreatment to control moisture content and then melt-spun, a surgical suture, a molded filler, a scaffold for tissue engineering It is possible to produce a sodium hyaluronate fiber which can be used as a raw material of the present invention, thereby completing the present invention.

본 발명의 목적은 생체 적합성과 피부 탄력능 및 수분 보유력이 뛰어난 히알루론산염을 주성분으로 하는 히알루론산염 파이버 및 이의 제조방법을 제공하는데 있다.It is an object of the present invention to provide a hyaluronate fiber composed mainly of a hyaluronate having excellent biocompatibility, skin elasticity and water retention ability and a method for producing the same.

본 발명의 다른 목적은 안전성 및 생체 적합성이 우수한 히알루론산염 파이버로 제조된 수술용 봉합사, 성형 필러, 리프팅용 실 및 조직 공학용 세포지지체(Scaffold)를 제공하는데 있다.
Another object of the present invention is to provide a surgical suture, a molded filler, a lifting thread and a scaffold for tissue engineering, which are manufactured from hyaluronic acid fiber having excellent safety and biocompatibility.

상기 목적을 달성하기 위하여, 본 발명은 (a) 분자량이 500~3,000kDa인 히알루론산염의 수분 함량을 5~20%로 조절하는 단계; (b) 수분 함량이 조절된 히알루론산염을 용융방사 장치에 넣고, 150~200℃로 가열 후, 고압방사하여 히알루론산염 파이버를 제조하는 단계; 및 (c) 히알루론산염 파이버를 에탄올 수용액에 침지시켜 표면을 경화시키는 단계를 포함하는 용융 방사에 의한 히알루론산염 파이버의 제조방법을 제공한다.In order to accomplish the above object, the present invention provides a method for producing a hyaluronic acid, comprising: (a) adjusting the water content of a hyaluronic acid salt having a molecular weight of 500 to 3,000 kDa to 5 to 20%; (b) preparing a hyaluronate fiber by heating the hyaluronate having a controlled moisture content in a melt-spinning apparatus at a temperature of 150 to 200 ° C and spinning at a high pressure; And (c) immersing the hyaluronate fiber into an ethanol aqueous solution to cure the surface. The present invention also provides a method for producing a hyaluronate fiber by melt spinning.

본 발명에 있어서, 상기 히알루론산염의 pH는 6~8인 것을 특징으로 한다.In the present invention, the pH of the hyaluronic acid salt is 6 to 8.

본 발명에 있어서, 상기 표면을 경화시키는 단계는 에탄올 수용액에서 1회 침지 또는 에탄올 수용액의 에탄올 농도를 순차적으로 증가시키면서 2~5회 침지시키는 것을 특징으로 한다.In the present invention, the step of curing the surface is characterized in that the substrate is immersed once in the aqueous solution of ethanol or immersed twice or five times while increasing the ethanol concentration of the aqueous solution of ethanol.

본 발명에 있어서, 상기 에탄올 수용액의 농도는 30~99부피%인 것을 특징으로 한다.In the present invention, the concentration of the aqueous ethanol solution is 30 to 99% by volume.

본 발명은 또한, 상기 방법으로 제조된 히알루론산염 파이버를 제공한다.The present invention also provides a hyaluronate fiber produced by the above method.

본 발명은 또한, 상기 히알루론산염 파이버를 포함하는 수술용 봉합사, 성형 필러, 리프팅용 실 및 조직 공학용 세포 지지체(Scaffold)를 제공한다.
The present invention also provides a surgical suture, a molded filler, a lifting thread, and a cellular scaffold for tissue engineering comprising the hyaluronate fiber.

본 발명의 히알루론산염 파이버는 히알루론산염을 주성분으로 제조되어, 안전성(Safety) 및 생체 적합성이 뛰어날 뿐만 아니라, 통상의 액상 하이드로겔 제품과 달리 미생물 오염이 없고, 관리 및 사용이 쉬워서 다양한 형태의 조직 수복용 제제로 이용할 수 있다. The hyaluronic acid fiber of the present invention is mainly composed of a hyaluronic acid salt and is not only excellent in safety and biocompatibility but also free from microbial contamination unlike ordinary liquid hydrogel products and easy to be managed and used, It can be used as a preparation for tissue repair.

또한, 본 발명의 히알루론산염 파이버는 고체 형태의 제품이라 히알루론산염 농도 대비 체적 볼륨이 매우 작아 체내 투입 시 환자의 고통과 불편을 최소화시켜 치료 효과를 극대화 할 수 있는 장점이 있다.
In addition, since the hyaluronic acid fiber of the present invention is a solid product, the volume of the hyaluronic acid salt is very small relative to the hyaluronate concentration, thereby minimizing the patient's pain and inconvenience when injected into the body, thereby maximizing the therapeutic effect.

도 1은 본 발명에서 사용한 용융방사 장치(Spinning Apparatus)의 설명도이다.
도 2는 고분자의 히알루론산염의 수분 함량 조정 전과 수분 함량 10%로 조정한 후 측정한 DSC 결과이다. 1 is an explanatory diagram of a spinning apparatus used in the present invention.
Fig. 2 shows DSC results obtained after adjusting the moisture content of the hyaluronate of the polymer and adjusting the water content to 10%.

본 발명에서는 강한 수소 결합으로 인하여 용융이 안되는 히알루론산염을 습윤 처리시킬 경우 용융 방사가 가능하여 고함량의 히알루론산염을 포함하는 히알루론산염 파이버를 제조할 수 있다는 것과 표면 강화 단계를 통하여 히알루론산염 파이버의 물성을 조절할 수 있다는 것을 확인하고, 본 발명을 완성하게 되었다. In the present invention, when a hyaluronic acid salt which is not melted due to strong hydrogen bonding is subjected to wet treatment, it is possible to produce a hyaluronate fiber containing a high content of hyaluronate by melt spinning, It is confirmed that the physical properties of the acid salt fiber can be controlled, and the present invention has been completed.

본 발명의 일 실시예에서는 수분 함량이 조절된 히알루론산나트륨의 용융에 기인한 흡열 피크를 열분석기 (Differential Scanning Calorimeter) (DSC) 측정을 통해 확인하고, 측정 결과를 참조하여 히알루론산나트륨 내의 수분 함량을 5~20%로 조절 후, 150~200℃에서 용융 방사하여 히알루론산나트륨 파이버(Fiber)를 제조하였다. 그리고, 물성을 향상시키기 위하여 히알루론산나트륨 파이버를 50%, 70% 및 95% 에탄올 수용액에 순차적으로 침지시켜 표면을 경화시켜 히알루론산염 파이버(Fiber)를 제조하였다. In one embodiment of the present invention, an endothermic peak due to melting of sodium hyaluronate with controlled moisture content is confirmed by a differential scanning calorimeter (DSC) measurement, and the moisture content in the sodium hyaluronate Was adjusted to 5 to 20%, and then melt-spun at 150 to 200 ° C to prepare a sodium hyaluronate fiber. In order to improve the physical properties, sodium hyaluronate fiber was sequentially immersed in 50%, 70% and 95% aqueous ethanol solution to cure the surface to prepare a hyaluronic acid fiber.

그 결과, 제조된 히알루론산나트륨 파이버(Fiber)는 식염수에 장시간 침지하여도 물성과 형태 유지가 가능하다는 것을 확인하였다. As a result, it was confirmed that the manufactured hyaluronic acid sodium fiber can maintain its physical properties and shape even when it is immersed in saline for a long time.

따라서, 본 발명은 일 관점에서, (a) 분자량이 500~3,000kDa인 히알루론산염의 수분 함량을 5~20%로 조절하는 단계; (b) 수분 함량이 조절된 히알루론산염을 용융방사 장치에 넣고, 150~200℃로 가열 후, 고압방사하여 히알루론산염 파이버를 제조하는 단계; 및 (c) 히알루론산염 파이버를 에탄올 수용액에 침지시켜 표면을 경화시키는 단계를 포함하는 용융 방사에 의한 히알루론산염 파이버의 제조방법에 관한 것이다.Accordingly, in one aspect, the present invention provides a method for preparing a hyaluronic acid salt, comprising: (a) adjusting the water content of a hyaluronate having a molecular weight of 500 to 3,000 kDa to 5 to 20%; (b) preparing a hyaluronate fiber by heating the hyaluronate having a controlled moisture content in a melt-spinning apparatus at a temperature of 150 to 200 ° C and spinning at a high pressure; And (c) immersing the hyaluronate fibers in an aqueous ethanol solution to cure the surface of the hyaluronate fibers.

본 발명에 있어서, 히알루론산염은 히알루론산에 염이 결합되어 있는 것으로서, 히알루론산나트륨, 히알루론산칼슘, 히알루론산칼륨 등을 예시할 수 있으나 이에 한정되는 것은 아니다.In the present invention, the hyaluronic acid salt is a salt in which hyaluronic acid is bound, and examples thereof include sodium hyaluronate, calcium hyaluronate, and potassium hyaluronate, but are not limited thereto.

상기 히알루론산염의 수분 함량 조절은 히알루론산염의 수분을 조절할 수 있는 것이라면 그 방법에 제한없이 수행이 가능하다. 예를 들어, 항온 항습기를 이용하여 히알루론산염의 수분을 조절할 수 있다. The moisture content of the hyaluronic acid salt can be controlled without limitation as long as it can control the moisture content of the hyaluronic acid salt. For example, the moisture of the hyaluronate can be controlled by using a thermostat.

히알루론산염 내의 수분 함량이 5% 미만인 경우 고온 고압 하에서 용융 방사에 의한 방사(Spinning)시 용융의 곤란으로 인하여 방사(Spinning)에 어려움이 있고, 히알루론산염 내의 수분 함량이 20%를 초과할 경우 방사(Spinning) 후 파이버(fiber) 내 높은 수분 함유량으로 인해 경화 과정 후에도 Fiber의 형태 유지가 곤란한 문제점이 있다.When the moisture content in the hyaluronate is less than 5%, spinning is difficult due to the difficulty of melting during spinning under high temperature and high pressure, and when the moisture content in the hyaluronate exceeds 20% There is a problem that it is difficult to maintain the shape of the fiber even after the curing process due to a high moisture content in the fiber after spinning.

본 발명에서는 수분 함량이 5~20%로 조절된 히알루론산염을 용융방사 장치(도 1 참조)의 용융 저장부(melt reservior)에 넣고, 150~200℃로 가열 후, 고압방사 시켜 히알루론산염 파이버를 제조하는 것을 특징으로 한다.In the present invention, hyaluronate having a moisture content adjusted to 5 to 20% is placed in a melt reservoir of a melt spinning apparatus (see FIG. 1), heated at 150 to 200 ° C, Thereby producing a fiber.

본 발명에 따른 히알루론산염 파이버는 히알루론산염 단독으로 제조가 가능하지만, 활용 분야에 따라 당 업계에서 통상적으로 이용되는 담체 또는 부형제 성분들을 추가로 포함할 수 있고, 그 종류 및 함량 범위가 특별히 한정되는 것은 아니다. The hyaluronate fiber according to the present invention may be prepared by using hyaluronate alone, but may further include carrier or excipient components commonly used in the art depending on the field of application, and the kind and content range thereof is specifically limited It is not.

본 발명의 주요 용도인 조직 수복용 제제로 활용 시 보다 강화된 물성과 기능성 확보를 위하여 약리학적으로 허용되는 생체 적합성 제제인 셀룰로오스계 소재와 분해성이 우수한 고분자인 폴리에틸렌, 폴리다이옥산, 폴리비닐 알콜, 폴리비닐에테르, 폴리비닐 피롤리돈, 폴리락틱산 등을 히알루론산과 혼합하여 방사(Spinning)하여 제조할 수 있다.
In order to provide enhanced physical properties and functionality when used as a tissue regeneration preparation, which is a main application of the present invention, cellulose-based materials, which are pharmacologically acceptable biocompatible agents, and polymers having excellent decomposability such as polyethylene, polydioxane, polyvinyl alcohol, poly Vinyl ether, polyvinyl pyrrolidone, polylactic acid, etc., with hyaluronic acid and spinning the mixture.

히알루론산염을 용융 방사하고, 건조시켜 제조한 히알루론산염 파이버를 그대로 사용할 경우 히알루론산 자체의 수분 민감성으로 인하여 보관과 물성 유지가 어려운 안정성(Stability) 문제가 있다.When the hyaluronate fiber prepared by melt-spinning and drying the hyaluronate is used as it is, the hyaluronic acid itself has a problem of stability that is difficult to maintain and maintain due to moisture sensitivity of the hyaluronic acid itself.

따라서, 이러한 문제를 해결하기 위하여 본 발명에서는 제조된 히알루론산염 파이버를 에탄올 수용액에 침지시켜 표면을 경화시키는 것을 특징으로 한다.Accordingly, in order to solve such a problem, the present invention is characterized in that the surface of the hyaluronate fiber is immersed in an aqueous solution of ethanol to cure the surface.

히알루론산나트륨 파이버 표면의 경화는 90~99부피%의 에탄올 수용액에서 1회 침지(침지 시간 1초 내외)시키거나 에탄올 수용액의 에탄올 농도를 순차적으로 증가시키면서 2~5회 침지시키는 것 (침지 시간 1초 내외)을 특징으로 한다. The curing of the surface of sodium hyaluronate fiber is carried out by immersing once (immersing time about 1 second) in 90 to 99 volume% aqueous ethanol solution or 2 to 5 times immersion while increasing ethanol concentration of ethanol aqueous solution (immersion time 1 Seconds).

표면 경화를 위하여 사용되는 에탄올 수용액의 농도는 30~99부피%를 이용할 수 있고, 50~95부피%인 것이 바람직하다.The concentration of the aqueous ethanol solution used for surface hardening may be 30 to 99% by volume, preferably 50 to 95% by volume.

또한, 본 발명에서는 표면 경화된 히알루론산나트륨 파이버를 글루타르알데히드(glutaraldehyde), 에피클로로히드린(epychlorohydrin) 등의 가교 합성 화학물질의 수용액이나 키토산(chitosan), 폴리라이신(polylysine) 등의 수용화시 양이온성을 띄는 천연 고분자 물질의 수용액에 침지시켜 표면을 가교시키는 단계를 추가로 포함하는 것을 특징으로 한다. 이렇게 표면이 일부 가교된 히알루론산나트륨 파이버는 분해 저항성 및 기계적 물성이 향상될 수 있다.
Also, in the present invention, the surface-hardened sodium hyaluronate fiber is subjected to water-soluble treatment such as aqueous solution of a crosslinked synthetic chemical such as glutaraldehyde, epichlorohydrin, etc., chitosan, polylysine, Further comprising the step of crosslinking the surface by immersing it in an aqueous solution of a natural high molecular substance having a cationic property. The sodium hyaluronate fiber having a partially cross-linked surface can improve decomposition resistance and mechanical properties.

본 발명은 다른 관점에서 상기 방법으로 제조된 히알루론산염 파이버에 관한 것이다. The present invention relates to a hyaluronate fiber produced by this method from another aspect.

본 발명에 따라 제조된 히알루론산염 파이버는 히알루론산염 100% 순도로 제조가 가능하며, 표면이 단단하게 경화 또는 가교되어 있어 기존의 액상 히알루론산염 조직 수복용 제품과 달리 미생물 오염이 없고, 관리 및 사용이 쉬워서 다양한 형태의 조직 수복용 제제로 이용될 수 있다. The hyaluronate fibers prepared according to the present invention can be prepared with hyaluronate 100% purity and hardened or crosslinked on the surface thereof. Therefore, unlike conventional products for recovering liquid hyaluronate tissue, there is no microbial contamination, And are easy to use and can be used as various forms of tissue restorative agents.

따라서, 본 발명은 또 다른 관점에서 상기 히알루론산염 파이버를 포함하는 수술용 봉합사, 성형 필러, 리프팅용 실 및 조직 공학용 세포 지지체(Scaffold)에 관한 것이다.
Accordingly, the present invention relates to a surgical suture, a molded filler, a lifting thread, and a scaffold for tissue engineering, which comprises the hyaluronate fiber from a different viewpoint.

[실시예][Example]

이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for illustrating the present invention and that the scope of the present invention is not construed as being limited by these embodiments.

실시 예 1: 습윤 처리를 통한 HA Paste 제조Example 1: Production of HA paste by wet treatment

분자량 1.2MDa인 히알루론산나트륨 (Hi-AquaTM, (주)진우바이오)을 항온항습기를 사용하여 습윤 처리하였다. 즉, 상대 습도 60%의 조건 하에서 히알루론산나트륨 10g 기준으로 1~3시간 방치하여 히알루론산나트륨 내의 수분 함량을 5~30%로 조정하였다. 참고로, 습윤 처리 전 HA내의 수분 함량은 2% 정도였다.
Sodium hyaluronate (Hi-Aqua TM , manufactured by JinWoo Bio Co., Ltd.) having a molecular weight of 1.2 MDa was subjected to wet treatment using a thermostat. That is, under the condition of relative humidity of 60%, it was left for 1 to 3 hours based on 10 g of sodium hyaluronate to adjust the water content in sodium hyaluronate to 5 to 30%. For reference, the moisture content in the HA before wet treatment was about 2%.

실험 예 1: 열 분석기 (DSC) 측정 Experimental Example 1: Measurement of thermal analysis (DSC)

열 분석기(DSC6100, Seiko, Japan)를 이용하여 30~250℃ 온도범위, 10℃/min의 승온속도 조건에서 습윤 처리 전의 히알루론산나트륨과 실시예 1에서 습윤 처리한 히알루론산나트륨의 흡열 피크를 측정하였다. DSC 측정 결과, 습윤 처리가 안 된 히알루론산나트륨 분말의 경우 용융에 기인한 흡열 피크가 전혀 감지되지 않은 반면, 수분 함량이 5% 이상으로 조정된 히알루론산나트륨의 경우 온도 구간 도시 150~200℃ 부근에서 용융에 기인한 흡열 피크가 강하게 감지됨을 확인 할 수 있었다. 따라서, 상기 온도 구간에서 히알루론산나트륨의 용융 방사가 가능함을 알 수 있었다.
The endothermic peaks of sodium hyaluronate before wet treatment and sodium hyaluronate wetted in Example 1 were measured at a temperature range of 30 to 250 ° C and a temperature raising rate of 10 ° C / min using a thermal analyzer (DSC6100, Seiko, Japan) Respectively. As a result of the DSC measurement, in the case of sodium hyaluronate powder not subjected to wet treatment, no endothermic peak due to melting was observed, whereas in the case of sodium hyaluronate whose moisture content was adjusted to 5% or more, It was confirmed that the endothermic peak due to melting was strongly detected. Therefore, it was found that melt spinning of sodium hyaluronate was possible in the temperature range.

실시 예 2: 용융 방사에 의한 HA Fiber 제조Example 2: Production of HA fiber by melt spinning

실시 예 1에서 습윤 처리한 히알루론산나트륨을 용융방사 장치(Melt Spinning Apparatus)의 용융 저장부에 넣고, 이를 150~200℃에서 질소압 처리하여 방사(spinning)시킨 다음, 상온에서 일반 건조하여 히알루론산나트륨 파이버(HA Fiber)를 제조하였다.
Sodium hyaluronate wet treated in Example 1 was placed in a melt storage unit of a melt spinning apparatus and spin-treated at a temperature of 150 to 200 ° C by nitrogen pressure, and then dried at room temperature to obtain hyaluronic acid Sodium fiber (HA Fiber).

실시 예 3: 용융 방사 및 표면경화에 의한 HA Fiber 제조Example 3: Production of HA fiber by melt spinning and surface hardening

실시 예 2와 동일한 방법으로 방사(spinning)시켜 제조한 HA Fiber를 50% 에탄올, 70% 에탄올, 최종 95% 에탄올에 차례로 침지시켜 표면을 경화 후 상온에서 일반 건조하여 히알루론산나트륨 파이버(HA Fiber)를 제조하였다.
HA Fiber prepared by spinning in the same manner as in Example 2 was immersed in 50% ethanol, 70% ethanol and final 95% ethanol in order to cure the surface, and then dried at room temperature to obtain HA fiber, .

실시 예 4: 용융 방사 및 표면경화에 의한 HA Fiber 제조Example 4: Production of HA fiber by melt spinning and surface hardening

실시 예 2와 동일한 방법으로 방사(spinning)시켜 제조한 HA Fiber를 95% 에탄올에 바로 침지시켜 표면을 경화 후 상온에서 일반 건조하여 히알루론산나트륨 파이버(HA Fiber)를 제조하였다.
HA fiber prepared by spinning in the same manner as in Example 2 was immediately immersed in 95% ethanol to harden the surface, and then dried at room temperature to prepare HA fiber.

실시 예 5: 용융 방사 및 표면경화에 의한 HA Fiber 제조Example 5: HA fiber production by melt spinning and surface hardening

실시 예 2와 동일한 방법으로 방사(spinning)시켜 제조한 HA Fiber를 50% 에탄올에 바로 침지시켜 표면을 경화 후 상온에서 일반 건조하여 히알루론산나트륨 파이버(HA Fiber)를 제조하였다.
The HA fiber prepared by spinning in the same manner as in Example 2 was immediately immersed in 50% ethanol to harden the surface, and then dried at room temperature to produce HA fiber.

실험 예 2: 수분 팽윤도 (Swelling Ratio) 측정 Experimental Example 2: Measurement of Swelling Ratio

실시 예 2~5에서 얻은 히알루론산나트륨 파이버(HA Fiber)를 37℃, 식염수에 침지시켜 시간에 따른 팽윤 속도를 측정하고, 그 결과를 표 1에 나타내었다. The hyaluronic acid sodium fiber (HA Fiber) obtained in Examples 2 to 5 was immersed in saline at 37 占 폚 to measure swelling speed with time, and the results are shown in Table 1.

참고로, 팽윤 속도는 다음의 식으로 구하였다.For reference, the swelling speed was obtained by the following equation.

팽윤 속도(%) = (일정 시간 경과 후 HA Fiber 무게/초기 Fiber 무게) X 100
Swelling rate (%) = (HA fiber weight / initial fiber weight after a certain time) X 100

팽윤도 (%)Swelling (%) 1hr1hr 2hr2 hr 3hr3hr 5hr5hr 12hr12hr 24hr24hr 실시예 2Example 2 138138 -- -- -- -- -- 실시예 3Example 3 111111 118118 123123 128128 135135 148148 실시예 4Example 4 108108 115115 119119 123123 130130 141141 실시예 5Example 5 125125 138138 143143 -- -- --

표 1에 나타난 바와 같이, 표면 경화가 이루어지지 않은 실시예 2의 히알루론산나트륨 파이버(HA Fiber)는 식염수 침지 2시간 경과 시 파이버(Fiber) 형태 유지 불가하여 팽윤도 측정이 불가하였다. As shown in Table 1, the hyaluronic acid sodium fiber (HA Fiber) of Example 2 in which surface hardening was not carried out was not able to maintain the fiber form in 2 hours after immersion in saline solution, and the swelling degree could not be measured.

30%, 50% 및 95% 에탄올 수용액으로 표면 경화된 실시예 3의 히알루론산나트륨 파이버(HA Fiber)는 식염수 침지 24시간 경과 후에도 팽윤도가 148% 정도로서 경화 과정에 의해 표면이 단단하게 경화되어 파이버(Fiber) 형태 유지가 가능함을 확인하였다. The hyaluronic acid sodium fiber (HA Fiber) of Example 3 surface-hardened with aqueous solutions of 30%, 50% and 95% ethanol had a degree of swelling of about 148% after 24 hours of immersion in saline so that the surface hardened by the curing process, Fiber) shape.

또한, 95% 에탄올 수용액으로 표면 경화된 실시예 4의 히알루론산나트륨 파이버(HA Fiber)는 식염수 침지 24시간 경과 후에도 파이버(Fiber) 형태가 유지되지만, 50% 에탄올 수용액으로 표면 경화된 실시예 5의 히알루론산나트륨 파이버(HA Fiber)는 식염수 침지 5시간 경과 시 파이버(Fiber) 형태 유지가 불가능함을 알 수 있었다.The hyaluronic acid sodium fiber (HA Fiber) of Example 4 surface-hardened with an aqueous 95% ethanol solution retained the fiber form even after 24 hours of immersion in saline solution, but the fiber form of Example 5 having a surface hardened with a 50% aqueous ethanol solution Hyaluronic acid sodium fiber (HA Fiber) was not able to maintain the fiber shape after 5 hours of immersion in saline solution.

이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적 기술은 단지 바람직한 실시 양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereto will be. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (9)

다음 단계를 포함하는 용융 방사에 의한 히알루론산염 파이버의 제조방법:
(a) 중량평균분자량이 500~3,000kDa인 히알루론산염의 수분 함량을 5~20%로 조절하는 단계;
(b) 수분 함량이 조절된 히알루론산염을 용융방사 장치에 넣고, 150~200℃로 가열 후, 고압방사하여 히알루론산염 파이버를 제조하는 단계; 및
(c) 히알루론산염 파이버를 에탄올 수용액에 침지시켜 표면을 경화시키는 단계.
A process for producing hyaluronate fibers by melt spinning comprising the steps of:
(a) adjusting the water content of the hyaluronate having a weight average molecular weight of 500 to 3,000 kDa to 5 to 20%;
(b) preparing a hyaluronate fiber by heating the hyaluronate having a controlled moisture content in a melt-spinning apparatus at a temperature of 150 to 200 ° C and spinning at a high pressure; And
(c) immersing the hyaluronate fiber in an aqueous ethanol solution to cure the surface.
제1항에 있어서, 상기 히알루론산염의 pH는 6~8인 것을 특징으로 하는 히알루론산염 파이버의 제조방법.
The method according to claim 1, wherein the hyaluronate has a pH of 6 to 8.
제1항에 있어서, 상기 표면을 경화시키는 단계는 에탄올 수용액에서 1회 침지 또는 에탄올 수용액의 에탄올 농도를 순차적으로 증가시키면서 2~5회 침지시키는 것을 특징으로 하는 히알루론산염 파이버의 제조방법.
The method according to claim 1, wherein the step of curing the surface comprises immersing the substrate in an aqueous ethanol solution for one time or dipping the substrate twice to five times while increasing the ethanol concentration of the aqueous ethanol solution.
제1항에 있어서, 상기 에탄올 수용액의 농도는 30~99부피%인 것을 특징으로 하는 히알루론산염 파이버의 제조방법.
The method of producing a hyaluronate fiber according to claim 1, wherein the concentration of the aqueous ethanol solution is 30 to 99% by volume.
제1항 내지 제4항중 어느 한 항의 방법으로 제조되고, 중량평균분자량 500~3,000kDa인 히알루론산염이 100% 순도로 함유된 것을 특징으로 하는 히알루론산염 파이버.
5. A hyaluronate fiber produced by the method of any one of claims 1 to 4, wherein the hyaluronate having a weight average molecular weight of 500 to 3,000 kDa is contained at a purity of 100%.
제5항의 히알루론산염 파이버를 포함하는 수술용 봉합사.
A surgical suture comprising the hyaluronate fiber of claim 5.
제5항의 히알루론산염 파이버를 포함하는 성형 필러.
A molded filler comprising the hyaluronate fiber of claim 5.
제5항의 히알루론산염 파이버를 포함하는 리프팅용 실.
A lifting yarn comprising the hyaluronate fiber of claim 5.
제5항의 히알루론산염 파이버를 포함하는 조직 공학용 세포 지지체 (Scaffold).
A tissue engineering cell scaffold comprising the hyaluronate fiber of claim 5.
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